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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 45931

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Prof. Dr. Malgorzata Wasniewska

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Guest Editor

Department of Human Pathology of Adult- and Childhood, University of Messina, Messina, Italy
Interests: pediatric endocrinology; autoimmune diseases
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Prof. Dr. Artur Bossowski

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Department of Pediatrics, Endocrinology, Diabetology with Cardiology Unit, Medical University of Bialystok, 15-274 Bialystok, Poland
Interests: genetic pathomechanisms in autoimmune diseases; pediatric endocrinology; diabetology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autoimmune diseases (ADs) are characterized by a multifactorial etiology, in which genetic and environmental factors are responsible for the loss of immunological tolerance.
The different genetic factors could be associated not only with disease susceptibility but also with specific autoantibodies and disease phenotypes. The recognition of specific genetic variants might help us to better understand ADs' pathogenic mechanisms and identify patients with a more aggressive clinical course of disease. Knowledge of new aspects of ADs could help us to better understand disease etiology and treatment response and also contribute to the development of new therapies. The main objective of this Special Issue is to provide an update to the most important topics related to autoimmune disease genetics, with particular attention to organ-specific ones. In addition, we are interested in highlighting studies on comorbidities in ADs and their interrelations. Furthermore, we hope to carry out a comparison between researchers and clinicians with the aim of transferring the most recent innovations into daily practice, adopting shared lines of behavior, and, thus, strengthening the integration between these two groups.

This will be accomplished in the form of a collection of original research and systematic review articles.

Prof. Malgorzata Wasniewska
Prof. Artur Bossowski
Guest Editors

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Keywords

autoimmune disease
endocrine gland
genetic syndrome
genetic polymorphism
genetic pathomechanism

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Published Papers (12 papers)

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Editorial

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2 pages, 172 KiB

Open AccessEditorial

Special Issue: Autoimmune Disease Genetics

by Malgorzata Gabriela Wasniewska and Artur Bossowski

Genes 2021, 12(12), 1937; https://doi.org/10.3390/genes12121937 - 30 Nov 2021

Cited by 1 | Viewed by 2263

Abstract

Autoimmune diseases (ADs) are characterized by a multifactorial etiology, in which genetic and environmental factors are responsible for the loss of immunological tolerance [...] Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

Research

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12 pages, 1882 KiB

Open AccessArticle

Evaluating the Role of Circulating Dendritic Cells in Methimazole-Treated Pediatric Graves’ Disease Patients

by Aleksandra Starosz, Karolina Stożek, Marcin Moniuszko, Kamil Grubczak and Artur Bossowski

Genes 2021, 12(2), 164; https://doi.org/10.3390/genes12020164 - 26 Jan 2021

Cited by 3 | Viewed by 2046

Abstract

Graves’ disease (GD) is hyperthyroidism associated with organ-specific autoimmune inflammation. GD occurs more frequently in adults than in children; however, pediatric patients are a therapeutic challenge due to cycles of remissions and relapses requiring constant monitoring at every stage of treatment administered. Dendritic cells (DCs) are considered to be a link between innate and adaptive immunity. DCs, as antigen-presenting cells (APCs), are involved in antigen presentation to T lymphocytes, thereby initiating a shift towards effector cells. In accordance, DCs also participate in the modulation of tolerance to specific antigens. To date, the data on DCs’ role in Graves’ pathological processes are scarce. Therefore, here, we evaluated the frequencies and role of circulating DCs in GD pediatric patients treated with methimazole. Flow cytometric analysis was implemented to evaluate three subsets of dendritic cells and their correlation with clinical GD-related parameters. We found significantly higher levels of DC subsets in patients at diagnosis. Furthermore, methimazole treatment seemed to effectively reduce subsets of DCs, which, in addition, were found to differentially correlate with thyroid function. Our study shed new light on DCs’ role in the pediatric GD pathomechanism. Further studies are required for the mechanistic assessment of DCs’ exact role in disease progression and influence on thyroid function. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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20 pages, 3277 KiB

Open AccessArticle

Transcriptional Regulation of CD40 Expression by 4 Ribosomal Proteins via a Functional SNP on a Disease-Associated CD40 Locus

by Meijuan Zou, Xiaoyu Zhang, Danli Jiang, Yihan Zhao, Ting Wu, Qiaoke Gong, Hang Su, Di Wu, Larry Moreland and Gang Li

Genes 2020, 11(12), 1526; https://doi.org/10.3390/genes11121526 - 21 Dec 2020

Cited by 7 | Viewed by 3485

Abstract

Previously, using FREP-MS, we identified a protein complex including eight proteins that specifically bind to the functional SNP (fSNP) rs6032664 at a CD40 locus associated with autoimmune diseases. Among these eight proteins, four are ribosomal proteins RPL26, RPL4, RPL8, and RPS9 that normally make up the ribosomal subunits involved in the cellular process of protein translation. So far, no publication has shown these ribosomal proteins function as transcriptional regulators. In this work, we demonstrate that four ribosomal proteins: RPL26, RPL4, RPL8, and RPS9 are bona fide CD40 transcriptional regulators via binding to rs6032664. In addition, we show that suppression of CD40 expression by RPL26 RNAi knockdown inactivates NF-κB p65 by dephosphorylation via NF-κB signaling pathway in fibroblast-like synoviocytes (FLS), which further reduces the transcription of disease-associated risk genes such as STAT4, CD86, TRAF1 and ICAM1 as the direct targets of NF-κB p65. Based on these findings, a disease-associated risk gene transcriptional regulation network (TRN) is generated, in which decreased expression of, at least, RPL26 results in the downregulation of risk genes: STAT4, CD86, TRAF1 and ICAM1, as well as the two proinflammatory cytokines: IL1β and IL6 via CD40-induced NF-κB signaling. We believe that further characterization of this disease-associated TRN in the CD40-induced NF-κB signaling by identifying both the upstream and downstream regulators will potentially enable us to identify the best targets for drug development. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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15 pages, 1896 KiB

Open AccessArticle

Using Micro- and Macro-Level Network Metrics Unveils Top Communicative Gene Modules in Psoriasis

by Reyhaneh Naderi, Homa Saadati Mollaei, Arne Elofsson and Saman Hosseini Ashtiani

Genes 2020, 11(8), 914; https://doi.org/10.3390/genes11080914 - 10 Aug 2020

Cited by 3 | Viewed by 3099

Abstract

(1) Background: Psoriasis is a multifactorial chronic inflammatory disorder of the skin, with significant morbidity, characterized by hyperproliferation of the epidermis. Even though psoriasis’ etiology is not fully understood, it is believed to be multifactorial, with numerous key components. (2) Methods: In order to cast light on the complex molecular interactions in psoriasis vulgaris at both protein–protein interactions and transcriptomics levels, we studied a set of microarray gene expression analyses consisting of 170 paired lesional and non-lesional samples. Afterwards, a network analysis was conducted on the protein–protein interaction network of differentially expressed genes based on micro- and macro-level network metrics at a systemic level standpoint. (3) Results: We found 17 top communicative genes, all of which were experimentally proven to be pivotal in psoriasis, which were identified in two modules, namely the cell cycle and immune system. Intra- and inter-gene interaction subnetworks from the top communicative genes might provide further insight into the corresponding characteristic interactions. (4) Conclusions: Potential gene combinations for therapeutic/diagnostics purposes were identified. Moreover, our proposed workflow could be of interest to a broader range of future biological network analysis studies. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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7 pages, 243 KiB

Open AccessCommunication

Vitamin D Pathway Genetic Variation and Type 1 Diabetes: A Case–Control Association Study

by Joana T. Almeida, Dircea Rodrigues, Joana Guimarães and Manuel C. Lemos

Genes 2020, 11(8), 897; https://doi.org/10.3390/genes11080897 - 5 Aug 2020

Cited by 12 | Viewed by 2625

Abstract

Vitamin D has immunomodulatory effects, and its deficiency has been implicated in the autoimmune process of type 1 diabetes. Serum vitamin D levels are influenced by variants in genes involved in the synthesis, transport, hydroxylation and degradation of vitamin D. The aim of this study was to assess if single nucleotide polymorphisms (SNPs) at the DHCR7 (rs12785878), GC (rs2282679), CYP2R1 (rs2060793) and CYP24A1 (rs6013897) loci are associated with type 1 diabetes in the Portuguese population. Genotype and allele frequencies were determined in 350 cases of type 1 diabetes and in 490 controls. The frequency of each SNP alone was not significantly different between patients and controls. However, the combined analysis of the four SNPs showed that minor alleles of these variants clustered more frequently in patients. The proportion of individuals with three or more minor alleles was significantly higher in patients than in controls (56.3% vs. 48.5; odds ratio (OR) 1.37; 95% confidence interval (CI) 1.04–1.81; p-value 0.027). These results suggest a cumulative effect of SNPs at the DHCR7, GC, CYP2R1 and CYP24A1 loci on the susceptibility to type 1 diabetes, due to the roles of these genes in the vitamin D metabolic pathway. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

17 pages, 495 KiB

Open AccessArticle

GPR174 and ITM2A Gene Polymorphisms rs3827440 and rs5912838 on the X chromosome in Korean Children with Autoimmune Thyroid Disease

by Won Kyoung Cho, Hye-Ri Shin, Na Yeong Lee, Seul Ki Kim, Moon Bae Ahn, In-Cheol Baek, Tai-Gyu Kim and Byung-Kyu Suh

Genes 2020, 11(8), 858; https://doi.org/10.3390/genes11080858 - 27 Jul 2020

Cited by 11 | Viewed by 3135

Abstract

(1) Background: Autoimmune thyroid diseases (AITDs) are female predominant and much attention has been focused on G protein-coupled receptor 174 (GPR174) and integral membrane protein 2A (ITM2A) on the X chromosome as Grave’s disease (GD) susceptible locus. (2) Methods: We genotyped four single nucleotide polymorphisms (SNPs), rs3810712, rs3810711, rs3827440, and rs5912838, of GPR174 and ITM2A in 115 Korean children with AITD (M = 25 and F = 90; GD = 74 (14.7 ± 3.6 years), HD = 41 (13.4 ± 3.2 years); GD-thyroid-associated ophthalmopathy (TAO) = 40, GD-non-TAO=34) and 204 healthy Korean individuals (M = 104 and F = 100). The data were analyzed by sex-stratified or combined. (3) Results: Three SNPs, rs3810712, rs3810711 and rs3827440, were found to be in perfect linkage disequilibrium (D’ = 1, r² = 1). In AITD, HD, GD, GD-TAO, and GD-non-TAO patients, rs3827440 TT/T and rs5912838 AA/A were susceptible and rs3827440 CC/C and rs5912838 CC/C were protective genotypes. When analyzed by sex, rs3827440 TT and rs5912838 AA were susceptible and rs3827440 CC and rs5912838 CC were protective genotypes in female AITD, GD, GD-TAO, and GD-non-TAO subjects. In male AITD patients, rs3827440 T and rs5912838 A were susceptible and rs3827440 C and rs5912838 C were protective genotypes. (4) Conclusions: Polymorphisms in GPR174 and ITM2A genes on the X chromosome might be associated with AITD in Korean children. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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Review

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14 pages, 820 KiB

Open AccessReview

Pancreatic Associated Manifestations in Pediatric Inflammatory Bowel Diseases

by Ugo Cucinotta, Claudio Romano and Valeria Dipasquale

Genes 2021, 12(9), 1372; https://doi.org/10.3390/genes12091372 - 31 Aug 2021

Cited by 3 | Viewed by 3649

Abstract

Inflammatory bowel diseases (IBDs) are chronic relapsing inflammatory conditions of the gastrointestinal tract, encompassing Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U). They are currently considered as systemic disorders determined by a set of genetic predispositions, individual susceptibility and environmental triggers, potentially able to involve other organs and systems than the gastrointestinal tract. A large number of patients experiences one or more extraintestinal manifestations (EIMs), whose sites affected are mostly represented by the joints, skin, bones, liver, eyes, and pancreas. Pancreatic abnormalities are not uncommon and are often underestimated, encompassing acute and chronic pancreatitis, autoimmune pancreatitis, exocrine pancreatic insufficiency and asymptomatic elevation of pancreatic enzymes. In most cases they are the result of environmental triggers. However, several genetic polymorphisms may play a role as precipitating factors or contributing to a more severe course. The aim of this paper is to provide an updated overview on the available evidence concerning the etiology, pathogenesis and clinical presentation of pancreatic diseases in IBD pediatric patients. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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17 pages, 366 KiB

Open AccessReview

Ophthalmologic Manifestations of Primary Sjögren’s Syndrome

by Anna Maria Roszkowska, Giovanni William Oliverio, Emanuela Aragona, Leandro Inferrera, Alice Antonella Severo, Federica Alessandrello, Rosaria Spinella, Elisa Imelde Postorino and Pasquale Aragona

Genes 2021, 12(3), 365; https://doi.org/10.3390/genes12030365 - 4 Mar 2021

Cited by 27 | Viewed by 4104

Abstract

Sjögren’s syndrome (SS) is a chronic, progressive, inflammatory, autoimmune disease, characterized by the lymphocyte infiltration of exocrine glands, especially the lacrimal and salivary, with their consequent destruction. The onset of primary SS (pSS) may remain misunderstood for several years. It usually presents with different types of severity, e.g., dry eye and dry mouth symptoms, due to early involvement of the lacrimal and salivary glands, which may be associated with parotid enlargement and dry eye; keratoconjunctivitis sicca (KCS) is its most common ocular manifestation. It is still doubtful if the extent ocular surface manifestations are secondary to lacrimal or meibomian gland involvement or to the targeting of corneal and conjunctival autoantigens. SS is the most representative cause of aqueous deficient dry eye, and the primary role of the inflammatory process was evidenced. Recent scientific progress in understanding the numerous factors involved in the pathogenesis of pSS was registered, but the exact mechanisms involved still need to be clarified. The unquestionable role of both the innate and adaptive immune system, participating actively in the induction and evolution of the disease, was recognized. The ocular surface inflammation is a central mechanism in pSS leading to the decrease of lacrimal secretion and keratoconjunctival alterations. However, there are controversies about whether the ocular surface involvement is a direct autoimmune target or secondary to the inflammatory process in the lacrimal gland. In this review, we aimed to present actual knowledge relative to the pathogenesis of the pSS, considering the role of innate immunity, adaptive immunity, and genetics. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

13 pages, 5195 KiB

Open AccessReview

IPEX Syndrome: Genetics and Treatment Options

by Iwona Ben-Skowronek

Genes 2021, 12(3), 323; https://doi.org/10.3390/genes12030323 - 24 Feb 2021

Cited by 31 | Viewed by 5724

Abstract

(1) Background: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome characterizes a complex autoimmune reaction beginning in the perinatal period, caused by a dysfunction of the transcription factor forkhead box P3 (FOXP3). (2) Objectives: Studies have shown the clinical, immunological, and molecular heterogeneity of patients with IPEX syndrome. The symptoms, treatment, and survival were closely connected to the genotype of the IPEX syndrome. Recognition of the kind of mutation is important for the diagnostics of IPEX syndrome in newborns and young infants, as well as in prenatal screening. The method of choice for treatment is hematopoietic stem cell transplantation and immunosuppressive therapy. In children, supportive therapy for refractory diarrhea is very important, as well as replacement therapy of diabetes mellitus type 1 (DMT1) and other endocrinopathies. In the future, genetic engineering methods may be of use in the successful treatment of IPEX syndrome. (3) Conclusions: The genetic defects determine a diagnostic approach and prognosis, making the knowledge of the genetics of IPEX syndrome fundamental to introducing novel treatment methods. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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Graphical abstract

10 pages, 649 KiB

Open AccessReview

Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome

by Marta Ferrari and Stefano Stagi

Genes 2021, 12(2), 268; https://doi.org/10.3390/genes12020268 - 13 Feb 2021

Cited by 25 | Viewed by 3934

Abstract

Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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22 pages, 1211 KiB

Open AccessReview

Hashimoto’s Thyroiditis and Graves’ Disease in Genetic Syndromes in Pediatric Age

by Celeste Casto, Giorgia Pepe, Alessandra Li Pomi, Domenico Corica, Tommaso Aversa and Malgorzata Wasniewska

Genes 2021, 12(2), 222; https://doi.org/10.3390/genes12020222 - 4 Feb 2021

Cited by 26 | Viewed by 7779

Abstract

Autoimmune thyroid diseases (AITDs), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), are the most common cause of acquired thyroid disorder during childhood and adolescence. Our purpose was to assess the main features of AITDs when they occur in association with genetic syndromes. We conducted a systematic review of the literature, covering the last 20 years, through MEDLINE via PubMed and EMBASE databases, in order to identify studies focused on the relation between AITDs and genetic syndromes in children and adolescents. From the 1654 references initially identified, 90 articles were selected for our final evaluation. Turner syndrome, Down syndrome, Klinefelter syndrome, neurofibromatosis type 1, Noonan syndrome, 22q11.2 deletion syndrome, Prader–Willi syndrome, Williams syndrome and 18q deletion syndrome were evaluated. Our analysis confirmed that AITDs show peculiar phenotypic patterns when they occur in association with some genetic disorders, especially chromosomopathies. To improve clinical practice and healthcare in children and adolescents with genetic syndromes, an accurate screening and monitoring of thyroid function and autoimmunity should be performed. Furthermore, maintaining adequate thyroid hormone levels is important to avoid aggravating growth and cognitive deficits that are not infrequently present in the syndromes analyzed. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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Other

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7 pages, 209 KiB

Open AccessCase Report

Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes

by Andrea Carpino, Raffaele Buganza, Patrizia Matarazzo, Gerdi Tuli, Michele Pinon, Pier Luigi Calvo, Davide Montin, Francesco Licciardi and Luisa De Sanctis

Genes 2021, 12(2), 169; https://doi.org/10.3390/genes12020169 - 26 Jan 2021

Cited by 14 | Viewed by 2771

Abstract

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype–phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated. Full article

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